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  • 1
    Online Resource
    Online Resource
    Cytoglobin ligand binding regulated by changing haem-co-ordination in response to intramolecular disulfide bond formation and lipid interaction
    Portland Press Ltd. ; 2015
    In:  Biochemical Journal Vol. 465, No. 1 ( 2015-01-01), p. 127-137
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 465, No. 1 ( 2015-01-01), p. 127-137
    Abstract: Cytoglobin (Cygb) is a hexa-co-ordinate haem protein from the globin superfamily with a physiological function that is unclear. We have previously reported that the haem co-ordination is changed in the presence of lipids, potentially transforming the redox properties of the protein and hence the function of Cygb in vivo. Recent research suggests that the protein can exist in a number of states depending on the integrity and position of disulfide bonds. In the present study, we show that the monomeric protein with an internal disulfide bond between the two cysteine residues Cys38 and Cys83, interacts with lipids to induce a change in haem co-ordination. The dimeric protein with intermolecular disulfide bonds and monomeric protein without an intramolecular disulfide bond does not exhibit these changes in haem co-ordination. Furthermore, monomeric Cygb with an intramolecular disulfide bond has significantly different properties, oxidizing lipid membranes and binding ligands more rapidly as compared with the other forms of the protein. The redox state of these cysteine residues in vivo is therefore highly significant and may be a mechanism to modulate the biochemical properties of the haem under conditions of stress.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20140827
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2015
    detail.hit.zdb_id: 1473095-9
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  • 2
    Online Resource
    Online Resource
    Comparison of the oxidative reactivity of recombinant fetal and adult human hemoglobin: implications for the design of hemoglobin-based oxygen carriers
    Portland Press Ltd. ; 2018
    In:  Bioscience Reports Vol. 38, No. 4 ( 2018-08-31)
    Details
    In: Bioscience Reports, Portland Press Ltd., Vol. 38, No. 4 ( 2018-08-31)
    Abstract: Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been engineered to replace or augment the oxygen carrying capacity of erythrocytes. However, clinical results have generally been disappointing, in part due to the intrinsic oxidative toxicity of Hb. The most common HBOC starting material is adult human or bovine Hb. However, it has been suggested that fetal Hb may offer advantages due to decreased oxidative reactivity. Large-scale manufacturing of HBOC will likely and ultimately require recombinant sources of human proteins. We, therefore, directly compared the functional properties and oxidative reactivity of recombinant fetal (rHbF) and recombinant adult (rHbA) Hb. rHbA and rHbF produced similar yields of purified functional protein. No differences were seen in the two proteins in: autoxidation rate; the rate of hydrogen peroxide reaction; NO scavenging dioxygenase activity; and the NO producing nitrite reductase activity. The rHbF protein was: less damaged by low levels of hydrogen peroxide; less damaging when added to human umbilical vein endothelial cells (HUVEC) in the ferric form; and had a slower rate of intrinsic heme loss. The rHbA protein was: more readily reducible by plasma antioxidants such as ascorbate in both the reactive ferryl and ferric states; less readily damaged by lipid peroxides; and less damaging to phosphatidylcholine liposomes. In conclusion in terms of oxidative reactivity, there are advantages and disadvantages to the use of rHbA or rHbF as the basis for an effective HBOC.
    Type of Medium: Online Resource
    ISSN: 0144-8463 , 1573-4935
    URL: Article
    DOI: 10.1042/BSR20180370
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2018
    detail.hit.zdb_id: 2014993-1
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Lipid binding to cytoglobin leads to a change in haem co-ordination: a role for cytoglobin in lipid signalling of oxidative stress
    Portland Press Ltd. ; 2011
    In:  Biochemical Journal Vol. 434, No. 3 ( 2011-03-15), p. 483-492
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 434, No. 3 ( 2011-03-15), p. 483-492
    Abstract: Cytoglobin is a recently discovered hexa-co-ordinate haemoglobin that does not appear to function as a classical oxygen-binding protein. Its function is unknown and studies on the effects of changes in its expression have not decisively determined its role within the cell. In the present paper, we report that the protein is transformed from hexa-co-ordinate to penta-co-ordinate on binding a lipid molecule. This transformation occurs with the ferric oxidation state of the protein, but not the ferrous state, indicating that this process only occurs under an oxidative environment and may thus be related to redox-linked cell signalling mechanisms. Oleate binds to the protein in a 1:1 stoichiometry and with high affinity (Kd=0.7 μM); however, stopped-flow kinetic measurements yield a Kd value of 110 μM. The discrepancy between these Kd values may be rationalized by recognizing that cytoglobin is a disulfide-linked dimer and invoking co-operativity in oleate binding. The lipid-induced transformation of cytoglobin from hexa-co-ordinate to penta-co-ordinate does not occur with similar hexa-co-ordinate haemoglobins such as neuroglobin, and therefore appears to be a unique property of cytoglobin among the haemoglobin superfamily. The lipid-derived transformation may explain why cytoglobin has enhanced peroxidatic activity, converting lipids into various oxidized products, a property virtually absent from neuroglobin and much decreased in myoglobin. We propose that the binding of ferric cytoglobin to lipids and their subsequent transformation may be integral to the physiological function of cytoglobin, generating cell signalling lipid molecules under an oxidative environment.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20101136
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2011
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Mechanism of reaction of myoglobin with the lipid hydroperoxide hydroperoxyoctadecadienoic acid
    Portland Press Ltd. ; 1998
    In:  Biochemical Journal Vol. 330, No. 3 ( 1998-03-15), p. 1317-1323
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 330, No. 3 ( 1998-03-15), p. 1317-1323
    Abstract: The reaction between myoglobin and the lipid hydroperoxide 13(S)-hydroperoxy-9,11(cis,trans)-octadecadienoic acid (HPODE) was studied kinetically by spectrophotometric, polarographic and analytical methods. Metmyoglobin catalysed the decomposition of HPODE, resulting in peroxide, oxygen and conjugated diene depletion, together with the transient production of ferryl myoglobin. The reaction stoichiometry was 2:1:1 for peroxide to oxygen to conjugated diene, whereas the myoglobin remained generally intact. This stoichiometry and the rates of change of conjugated diene and ferryl myoglobin concentrations were not completely consistent with previously proposed mechanisms. We propose a novel mechanism in which HPODE reacts with both ferric myoglobin and ferryl myoglobin to form a redox cycle. Both peroxyl and alkoxyl radicals are produced, explaining the observed stoichiometry of peroxide, oxygen and conjugated diene depletion and the transient appearance of ferryl myoglobin. Computer simulation shows that this mechanism is fully capable of reproducing the observed time courses of all components.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj3301317
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 1998
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Ferryl haem protonation gates peroxidatic reactivity in globins
    Portland Press Ltd. ; 2007
    In:  Biochemical Journal Vol. 403, No. 3 ( 2007-05-01), p. 391-395
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 403, No. 3 ( 2007-05-01), p. 391-395
    Abstract: Ferryl (Fe(IV)=O) species are involved in key enzymatic processes with direct biomedical relevance; among others, the uncontrolled reactivities of ferryl Mb (myoglobin) and Hb (haemoglobin) have been reported to be central to the pathology of rhabdomyolysis and subarachnoid haemorrhage. Rapid-scan stopped-flow methods have been used to monitor the spectra of the ferryl species in Mb and Hb as a function of pH. The ferryl forms of both proteins display an optical transition with pK∼4.7, and this is assigned to protonation of the ferryl species itself. We also demonstrate for the first time a direct correlation between Hb/Mb ferryl reactivity and ferryl protonation status, simultaneously informing on chemical mechanism and toxicity and with broader biochemical implications.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20061421
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2007
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Engineering tyrosine electron transfer pathways decreases oxidative toxicity in hemoglobin: implications for blood substitute design
    Portland Press Ltd. ; 2016
    In:  Biochemical Journal Vol. 473, No. 19 ( 2016-10-01), p. 3371-3383
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 473, No. 19 ( 2016-10-01), p. 3371-3383
    Abstract: Hemoglobin (Hb)-based oxygen carriers (HBOC) have been engineered to replace or augment the oxygen-carrying capacity of erythrocytes. However, clinical results have generally been disappointing due to adverse side effects linked to intrinsic heme-mediated oxidative toxicity and nitric oxide (NO) scavenging. Redox-active tyrosine residues can facilitate electron transfer between endogenous antioxidants and oxidative ferryl heme species. A suitable residue is present in the α-subunit (Y42) of Hb, but absent from the homologous position in the β-subunit (F41). We therefore replaced this residue with a tyrosine (βF41Y, Hb Mequon). The βF41Y mutation had no effect on the intrinsic rate of lipid peroxidation as measured by conjugated diene and singlet oxygen formation following the addition of ferric(met) Hb to liposomes. However, βF41Y significantly decreased these rates in the presence of physiological levels of ascorbate. Additionally, heme damage in the β-subunit following the addition of the lipid peroxide hydroperoxyoctadecadieoic acid was five-fold slower in βF41Y. NO bioavailability was enhanced in βF41Y by a combination of a 20% decrease in NO dioxygenase activity and a doubling of the rate of nitrite reductase activity. The intrinsic rate of heme loss from methemoglobin was doubled in the β-subunit, but unchanged in the α-subunit. We conclude that the addition of a redox-active tyrosine mutation in Hb able to transfer electrons from plasma antioxidants decreases heme-mediated oxidative reactivity and enhances NO bioavailability. This class of mutations has the potential to decrease adverse side effects as one component of a HBOC product.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BCJ20160243
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2016
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Sugar beet hemoglobins: reactions with nitric oxide and nitrite reveal differential roles for nitrogen metabolism
    Portland Press Ltd. ; 2019
    In:  Biochemical Journal Vol. 476, No. 14 ( 2019-07-31), p. 2111-2125
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 476, No. 14 ( 2019-07-31), p. 2111-2125
    Abstract: In contrast with human hemoglobin (Hb) in red blood cells, plant Hbs do not transport oxygen, instead research points towards nitrogen metabolism. Using comprehensive and integrated biophysical methods we characterized three sugar beet Hbs: BvHb1.1, BvHb1.2 and BvHb2. Their affinities for oxygen, CO, and hexacoordination were determined. Their role in nitrogen metabolism was studied by assessing their ability to bind NO, to reduce nitrite (NiR, nitrite reductase), and to form nitrate (NOD, NO dioxygenase). Results show that BvHb1.2 has high NOD-like activity, in agreement with the high nitrate levels found in seeds where this protein is expressed. BvHb1.1, on the other side, is equally capable to bind NO as to form nitrate, its main role would be to protect chloroplasts from the deleterious effects of NO. Finally, the ubiquitous, reactive, and versatile BvHb2, able to adopt ‘open and closed forms’, would be part of metabolic pathways where the balance between oxygen and NO is essential. For all proteins, the NiR activity is relevant only when nitrite is present at high concentrations and both NO and oxygen are absent. The three proteins have distinct intrinsic capabilities to react with NO, oxygen and nitrite; however, it is their concentration which will determine the BvHbs’ activity.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BCJ20190154
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2019
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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